During its 1st funding cycle (2001-2006), GenoMEL, the melanoma genetics consortium, forged a common protocol for collection of biosample, phenotype and questionnaire information from melanoma families across the globe with the goal of better understanding the role of CDKN2A mutations in these families. At that time, GenoMEL also established two population-based case-control studies, one in the UK and one in Australia, both using identical collection methods. During its 2nd funding cycle (2006 - 2012), GenoMEL continued its research into high penetrance melanoma genetics through enhanced characterization of inherited CDKN2A mutations and a systematic search for novel high penetrance genes among CDKN2A (and CDK4) negative families. Concurrently at that time and supported by EU funds (2005-2011), GenoMEL also engaged in discovery of low penetrance susceptibility genes using a genome- wide scan approach. In this 3rd cycle R01 application, we seek to build off of information previously collected by GenoMEL over the past 10 years and propose a series of vitally important analytic questions focused on inherited genetics, sun exposure, and their combine effect. With the addition of limited and targeted new genotyping to be accomplished in this proposal, we seek to support novel analyses that will be undertaken by the continued collaborative efforts of members of the GenoMEL Analysis Team. First, we seek to determine the most informative SNPs or haplotypes in known melanoma susceptibility loci though imputation and modeling techniques. DNA samples from our UK and Australian population- based samples and our CDKN2A mutation carriers and non-carriers from our family-based study will be genotyped for a panel of these most informative SNPs/haplotypes. We will estimate the impact of these SNPs/haplotypes on melanoma risk separately in our population- based and multi-case family samples, and we will investigate whether these genetic effects are modified by different levels of cumulative and intermittent sun exposure measures in our study samples. Despite recent findings focused on genetic susceptibility to melanoma and our clear understanding of the importance of sun exposure to development of melanoma, the manner in which ultraviolet (UV) exposures come together with inherited genotypes and phenotypes to affect risk of melanoma remains poorly understood. GenoMEL is poised to address this knowledge gap.